Human Salivary Gland Stem Cells Functionally Restore Radiation Damaged Salivary Glands

Abstract

Adult stem cells are often touted as therapeutic agents in the regenerative medicine field, however data detailing both the engraftment and functional capabilities of solid tissue derived human adult epithelial stem cells is scarce. Here we show the isolation of adult human salivary gland (SG) stem/progenitor cells and demonstrate at the single cell level in vitro self-renewal and differentiation into multilineage organoids. We also show in vivo functionality, long-term engraftment, and functional restoration in a xenotransplantation model. Indeed, transplanted human salisphere-derived cells restored saliva production and greatly improved the regenerative potential of irradiated SGs. Further selection for c-Kit expression enriched for cells with enhanced regenerative potencies. Interestingly, interaction of transplanted cells with the recipient SG may also be involved in functional recovery. Thus, we show for the first time that salispheres cultured from human SGs contain stem/progenitor cells capable of self-renewal and differentiation and rescue of saliva production. Our study underpins the therapeutic promise of salisphere cell therapy for the treatment of xerostomia. STEM CELLS 2016;34:640-652 SIGNIFICANCE STATEMENTThis study describes the isolation, cultivation, and clinical potential of human salivary gland stem cells to treat radiation-induced xerostomia. We show the ability of human salivary gland derived cells to self-renew and differentiate in vitro and functionally restore irradiated salivary glands after xenotransplantation. The study is the final step toward clinical application.

Stem Cell Regenerative Therapy in Oral and Maxillofacial Region: A Systematic Review.

“…Pringle et al in 2016 (65) , showed engrafment and functional capabilities of human adult epithelial stem cells in salivary gland demonstatrd in vitro self renewal and differentiation into multilineage organoids. He also showed in vivo functionality, long term engrafment and functional restoration in Xenotransplantation model.…”

Three‐Dimensional Bioprinting Nanotechnologies towards Clinical Application of Stem Cells and Their Secretome in Salivary Gland Regeneration

“…Since human salispheres do contain KIT+ cells, there is a potential for future clinical use of KIT+ cell subpopulations [22]. Recently, Pringle and others [13] have successfully transplanted human salispheres into irradiated mice restoring the salivary flow, particularly when these salispheres were positively selected for KIT. However, the subpopulation of KIT+ cells in human SGs is very limited being less than 0.4% of the total population in younger adults, and this number substantially decreases with aging [13].…”

“…Recently, Pringle and others [13] have successfully transplanted human salispheres into irradiated mice restoring the salivary flow, particularly when these salispheres were positively selected for KIT. However, the subpopulation of KIT+ cells in human SGs is very limited being less than 0.4% of the total population in younger adults, and this number substantially decreases with aging [13]. Moreover, these salispheres have a restricted in vitro self-renewal and proliferative capacities that confines their growth to 2-3 population doublings at earlier passages (P1–P4) [13].…”

“…Thus, novel and effective therapeutical strategies for SG hypofunction are required [10]. Due to the depletion of the self-renewable progenitor/stem cell pool during RT damage, cell-based therapies are essential not only to generate new saliva-secreting tissues [10–13] but also to potentially repair the damaged SG via the production and extracellular release of bioactive secretory proteins by transplanted cells [14–17]. This group of non-membrane-bound secretory proteins has been named the salivary secretome [18].…”

Understanding mechanisms yields novel approaches to reduce radiotherapy-related xerostomia

“…However, the size of the submandibular and sublingual glands and location of their main ducts make stem cell sparing approaches challenging. Therefore, the findings that in vitro expandable stem cells (6) representing a critical target localized in anatomical similar regions in different glands in various species (1,2) suggests that transplantation of stem cells may be a viable approach to rescue e.g., the submandibular gland (6,7).…”